Keystone Nano, in partnership with the University of Maryland Greenebaum Cancer Center (UMD-GCC), proposes a multi-site clinical evaluation of the Ceramide NanoLiposome (CNL) as a novel anti-cancer therapeutic. The overall objective of this project is to advance the CNL through a Phase I clinical trial. The results of this trial will support subsequent trials for the intended initial indication of hepatocellular carcinoma (HCC) as well as other cancer indications. HCC is one of the most frequent and deadly cancers worldwide and there are no current treatments, either approved or in clinical development, that substantially alter the course of disease for patients diagnosed with advanced HCC. The combination of synergistic mechanisms of action that result in specific and selective toxicity of the CNL towards cancerous cells, along with the distinct advantages afforded by liposomal delivery, make the CNL a unique and powerful potential alternative to current HCC therapies. Numerous preclinical studies indicate that the CNL is highly efficacious, inducing tumor regression in HCC models without systemic toxicity. The preclinical development portfolio for the CNL including evaluations of pharmacokinetics, biodistribution, metabolism, efficacy, safety and toxicology are either published or provided as Appendices of this application. To evaluate the clinical utility of the CNL, a team of NCI-designated Cancer Centers led by the UMD-GCC, in cooperation with NCI-designated Cancer Centers at the University of Virginia Cancer Center (UVACC) and the Fred Hollings Cancer Center at the Medical University of South Carolina (MUSC), has been assembled to conduct the proposed multi-site Phase I clinical trial. This open-label, dose escalation study is designed to establish the safety of the CNL and recommended parameters for a Phase II clinical trial. Specific Aims are to 1) Establish the safety and maximum tolerated dose (MTD) of the CNL, 2) Quantify the pharmacokinetic (PK) profile of the CNL in humans and 3) Examine disease parameters for evidence of anti-cancer response. If successful, this research will advance the CNL towards commercialization and realize the mission of the NIH to translate fundamental knowledge of living systems into applications that enhance health, reduce illness and lengthen life.